Brain tumor is a mass of unnecessary cells growing in the brain or central spine canal. There are two basic kinds of brain tumors—primary brain tumors and metastatic brain tumors. Primary brain tumors start and tend to stay, in the brain. Metastatic brain tumors begin as cancer elsewhere in the body and spread to the brain. Brain tumors are also classified as “benign” or “malignant” based on degree of malignancy or aggressiveness of a brain tumor. Depending on the degree of malignancy, tumors are classified into Grade I, Grade II, Grade III and Grade IV.
According to published reports, nearly 70,000 new cases of primary brain tumors are diagnosed each year and around 10% of these are children between the ages of 0-19. It is reported that brain and central nervous system tumors are the most common cancers among children ages 0-19. There are nearly 700,000 people in the United States living with a brain tumor. There are more than 120 types of brain tumors identified till date.
The main treatments for brain or spinal cord tumors are surgery, radiotherapy and chemotherapy. These treatments may be used alone or in combination. Chemotherapy uses anti-cancer drugs (cytotoxic agents) to destroy cancer cells. They work by disrupting the growth of cancer cells. Chemotherapy drugs can be delivered orally (by mouth as a pill or liquid), intravenously (by infusion into a vein), topically (as a cream on the skin), or through Injection or direct placement (via a lumbar puncture or device placed under the scalp).
Nitrosureas have been generally utilized as single agent treatment chemotherapy or in established combination therapy with other approved chemotherapeutic agents for many years against primary brain tumors. Nitrosourea includes chemotherapeutic agents such as Chlorozotocin (DCNU), Carmustine (BCNU), Lomustine (CCNU), Nimustine and Ranimustine. Amongst them, Carmustine (bischloroethyl nitrosurea, BCNU or BiCNU) is a one of the leading nitrosurea drug for treatment of brain cancers owing to its ability to cross blood-brain barrier and excellent activity against brain tumors.
Carmustine alkylates DNA and RNA, interfering with their synthesis and functions. It also binds and modifies (carbamoylates) glutathione reductase, which consequently leads to cell death. Chemically, it is 1,3-bis (2-chloroethyl)-1-nitrosourea and has the following structural formula:

Carmustine is highly soluble in alcohol and lipids but poorly soluble in water wherein it readily gets hydrolyzed in water at pH >6. Carmustine is commercially available as a sterile lyophilized powder for injection under the tradename BiCNU® and in single dose vials containing 100 mg of lyophilized powders of carmustine. Dehydrated alcohol is co-packaged with the active drug product as a sterile diluent for constitution. The lyophilized carmustine appears as a pale yellow dry flake or a dry congealed mass. Prior to injection, the lyophilized carmustine is reconstituted with a co-packed sterile diluent and the solution is then further diluted with water. The reconstitution results in a clear, colorless to yellowish solution which may be further diluted with 5% Dextrose Injection, USP. However, the infusion of ethanol in BiCNU® formulation causes infusion toxicity and hypersensitivity reactions in patients.
Further, the conventional lyophilized formulation of carmustine is associated with frequent and serious toxicity in the form of delayed myelosuppression, Further, following IV infusion, it is rapidly taken up by the tissues but has shown to be rapidly degraded, with no intact drug detectable after 15 minutes. Therefore, the drug is associated with high toxicity and low selectivity, which in turn reduces the application of this drug for treatment of cancer.
To overcome and/or to reduce such side effects, it is the need of the hour to device a more efficient drug delivery system which can increase pharmaceutical efficacy accompanied by the concomitant decrease of side effects.
Lipoidal drug delivery system is one of such promising tool to tackle the problems in prior use, as stated above and many researchers have tried to develop a lipoidal formulation of carmustine. Few of the published formulations are as follows:
CN101143130 relates to a parenteral formulation of carmustine in the form of a stable oil-in-water emulsion. The composition comprises of pharmaceutically effective amount of carmustine, oil, a surfactant and water for injection. The invention also discloses the method of preparation of the said oil-in-water emulsion.
CN1110134 relates to an injectable, liposomal formulation and the process for its preparation. In the disclosed process, the fat-soluble pharmaceutically active ingredient and the liposome matrix are dissolved in an organic solvent to obtain lipid-soluble liquor; or alternatively, only the liposome matrix is dissolved in the organic solvent, and then a water-soluble liquid pharmaceutically active ingredient is added to the lipid-soluble liquor. The organic solvent is then removed from the liquor by using vacuum drying method and then nitrogen gas is charged into it.
Further, CN101444482, provide sustained-release injectable formulations containing a nitrosourea drug, which comprises of sustained-release microspheres and solvents. The sustained-release microspheres each comprise an anticancer-active component selected from nitrosourea drugs (such as nimustine and carmustine) and/or topoisomerase inhibitors, and a sustained-release agent. The solvents are common solvents or special solvents containing suspending agent. However, such processes are complex and expensive.
CN 1683016 discloses a process for preparation carrier particles containing surface transferrin for glioma-targeted-chemotherapy. Biodegradable polymers like polylactic acid, polyglycolic acid, polycaprolactone or copolymer of lactic acid and glycolic acid and chemotherapeutic drugs such as carmustine, adriamycin or taxols are dissolved in acetone, acetonitrile or dimethyl sulfoxide; and the solution is emulsified in a solution of transferrin or combined with transferrin chemically after co-dialysis with cholesterol modified glucosan dialdehyde to prepare the drug-carrying polymer particle containing surface transferrin. Such particles may be injected into tumor cavity for targeted release of the drug.
Thus, there is a need for an improved, robust carmustine formulating process.